Despite intriguing roles for the Succinate receptor (Sucnr1) in inflammation, few studies have explored its role in hematopoiesis. Here, we show that low SUCNR1 represents a marker for reduced overall and progression-free survival in acute myeloid leukemia (AML) patients. Succinic acid, which displays Sucnr1-dependent and independent effects, promotes disease in mouse models of pre-leukemic myelopoiesis, AML and AML xenografts, expressing low SUCNR1. In vivo global or hematopoietic deletion of Sucnr1 induces expansion of hematopoietic stem and progenitor cells (HSPC) and hematopoiesis, whilst Sucnr1-tomato+ HSPC display restricted engraftment potential. Mechanistically, activation of Sucnr1 counterbalances the stimulatory effect of intracellular succinate in HSPC and preserves HSPC transcriptional programs via control of S100a8/S100a9. Blocking S100a9 with tasquinimod rescues the defects of Sucnr1 knock-out mice, and combined with a potent Sucnr1 agonist shows therapeutic value in AML mice. In AML xenografts, single-cell RNA-sequencing reanalyses confirm SUCNR1 as a therapeutic vulnerability in patients. Together, Sucnr1 signaling restricts hematopoiesis at least partially through HSPC and via control of S100a8/S100a9. Its dysregulation emerges as contributor to malignancy that opens therapeutic avenues for AML patients.

The hematopoietic stem cell (HSC) niche in the bone marrow (BM) supports HSC function, fate and numbers [1]. Sympathetic fibres innervate the BM and are components of the hematopoietic stem and progenitor cell (HSPC) niche [2]. Neuropathy of the HSPC niche is present and essential for disease development in experimental models of JAK2V617F+ myeloproliferative neoplasms (MPN) and MLL-AF9+ acute myeloid leukemia (AML), and it is present in the BM of human MPN and AML patients [3–6]. Neuropathy contributes to mutant HSC expansion and represents an effective therapeutic target to block disease progression in JAK2V617F+ MPN mice [3]. The sympathomimetic agonist mirabegron restored nestin+ cells and reduced reticulin fibrosis in MPN patients [7]. Here, we show that neuropathy of the HSPC niche emerges in two additional experimental models of hematological disease including pre-leukemic myelopoiesis driven by NRASG12D and lymphoma/lymphoblastic leukemia driven by p53 deletion. Neuropathy involves severe ultrastructural damage in NRASG12D+ mice and AML patients as shown by electron microscopy. When further reinforced chemically, neuropathy has a profound impact on the experimental NRASG12D mouse model, promoting myeloid bias, reducing HSPC numbers and inducing changes in the stem cell microenvironment that include reduced numbers of mesenchymal stromal cells (MSC) and increased presence of morphologically abnormal blood vessels in BM. Together, BM neuropathy is a prevalent factor in hematopoietic malignancies that involves important degradation of sympathetic fibres and contributes to disease in a different manner depending on the driver mutation. This should be taken in consideration in the clinic, given that chemotherapy induces neuropathy of the HSC niche [8] and it is the most frequent first line treatment for AML, acute lymphoblastic leukemia and MPN patients.

Here we explored the role of interleukin-1β (IL-1β) repressor cytokine, IL-1 receptor antagonist (IL-1rn), in both healthy and abnormal hematopoiesis. Low IL-1RN is frequent in acute myeloid leukemia (AML) patients and represents a prognostic marker of reduced survival. Treatments with IL-1RN and the IL-1β monoclonal antibody canakinumab reduce the expansion of leukemic cells, including CD34 + progenitors, in AML xenografts. In vivo deletion of IL-1rn induces hematopoietic stem cell (HSC) differentiation into the myeloid lineage and hampers B cell development via transcriptional activation of myeloid differentiation pathways dependent on NFκB. Low IL-1rn is present in an experimental model of pre-leukemic myelopoiesis, and IL-1rn deletion promotes myeloproliferation, which relies on the bone marrow hematopoietic and stromal compartments. Conversely, IL-1rn protects against pre-leukemic myelopoiesis. Our data reveal that HSC differentiation is controlled by balanced IL-1β/IL-1rn levels under steady-state, and that loss of repression of IL-1β signaling may underlie pre-leukemic lesion and AML progression.

The purpose of this review is to present the current knowledge on the clinical use of several forms of cell therapy in hematological malignancies and the preclinical models available for their study. In the context of allogeneic hematopoietic stem cell transplants, mesenchymal stromal cells are pursued to help stem cell engraftment and expansion, and control graft versus host disease. We further summarize the status of promising forms of cellular immunotherapy including CAR T cell and CAR NK cell therapy aimed at eradicating the cells of origin of leukemia, i.e., leukemia stem cells. Updates on other forms of cellular immunotherapy, such as NK cells, CIK cells and CAR CIK cells, show encouraging results in AML. The considerations in available in vivo models for disease modelling and treatment efficacy prediction are discussed, with a particular focus on their strengths and weaknesses for the study of healthy and diseased hematopoietic stem cell reconstitution, graft versus host disease and immunotherapy. Despite current limitations, cell therapy is a rapidly evolving field that holds the promise of improved cure rates, soon. As a result, we may be witnessing the birth of the hematology of tomorrow. To further support its development, improved preclinical models including humanized microenvironments in mice are urgently needed.

Acute myeloid leukaemia (AML) cells interact and modulate components of their surrounding microenvironment into their own benefit. Stromal cells have been shown to support AML survival and progression through various mechanisms. Nonetheless, whether AML cells could establish beneficial metabolic interactions with stromal cells is underexplored. By using a combination of human AML cell lines and AML patient samples together with mouse stromal cells and a MLL-AF9 mouse model, here we identify a novel metabolic crosstalk between AML and stromal cells where AML cells prompt stromal cells to secrete acetate for their own consumption to feed the tricarboxylic acid cycle (TCA) and lipid biosynthesis. By performing transcriptome analysis and tracer-based metabolic NMR analysis, we observe that stromal cells present a higher rate of glycolysis when co-cultured with AML cells. We also find that acetate in stromal cells is derived from pyruvate via chemical conversion under the influence of reactive oxygen species (ROS) following ROS transfer from AML to stromal cells via gap junctions. Overall, we present a unique metabolic communication between AML and stromal cells and propose two different molecular targets, ACSS2 and gap junctions, that could potentially be exploited for adjuvant therapy.

Chronic obstructive pulmonary disease (COPD) is characterised by inflammatory and oxidative alterations in the lung and extrapulmonary compartments, through involvement of the immune system. Several leukocyte functions are health markers and good predictors of longevity, and high pro-inflammatory and oxidative states are related to more aged profiles. Here, we aimed to investigate the aging rate in terms of immunosenescence in COPD men with respect to healthy age-matched controls. Several neutrophil (adherence, chemotaxis, phagocytosis, superoxide anion stimulated production) and lymphocyte (adherence, chemotaxis, lymphoproliferation, natural killer activity) functions, cytokine concentrations released in response to lipopolysaccharide (tumor necrosis factor-alpha, interleukin (IL)-6, IL-8, IL-10) and redox parameters (intracellular glutathione content, basal superoxide anion level) were assessed in circulating leukocytes of men with moderate and severe stages of COPD, and compared to healthy age-matched volunteers. The biological age or aging rate in each participant was determined using the values of leukocyte functions. The results indicated impairment of immune functions in COPD patients, both in innate and adaptive immunity, and higher pro-inflammatory and oxidative states in peripheral leukocytes than controls. In general, these changes were more remarkable at the severe stage of airway obstruction. Importantly, COPD patients were found to be aging at a faster rate than age-matched healthy counterparts.

Oxidized, damaged and misfolded proteins accumulate during aging and contribute to impaired cell function and tissue homeodynamics. Damaged proteins are degraded by cellular clearance mechanisms like the 20S proteasome. Aging relates to low 20S proteasome function, whereas long-lived species show high levels. However, contradictory results exist depending on the tissue or cell type and it is unknown how the 20S proteasome functions in exceptionally old mice. The aim of this study was to investigate two proteasome activities (caspase-like and chymotrypsin-like) in several tissues (lung, heart, axillary lymph nodes, liver, kidney) and cells (peritoneal leukocytes) from adult (28 ± 4 weeks, n = 12), old (76 ± 4 weeks, n = 9) and exceptionally old (128 ± 4 weeks, n = 9) BALB/c female mice. The results show different age-related changes depending on the tissue and the activity considered, so there is no universal decline in proteasome function with age in female mice. Interestingly, exceptionally old mice displayed better maintained proteasome activities, suggesting that preserved 20S proteasome is associated with successful aging.

Acute myeloid leukemia (AML) is a heterogeneous, complex, and deadly disease, whose treatment has hardly evolved for decades and grounds on the use of intensive chemotherapy regimens. Chemotherapy helps reduce AML bulk, but promotes relapse in the long-run by selection of chemoresistant leukemia stem cells (LSC). These may diversify and result in progression to more aggressive forms of AML.In vivomodels suggest that the bone marrow stem cell niche helps LSC stay dormant and protected from chemotherapy. Here, we summarize relevant changes in stem cell niche homing and adhesion of AML LSC vs. healthy hematopoietic stem cells, and provide an overview of clinical trials aiming at targeting these processes for AML treatment and future directions within this field. Promising results with various non-mutation-targeted novel therapies directed to LSC eradication via interference with their anchoring to the stem cell niche have encouraged on-going or future advanced phase III clinical trials. In the coming years, we may see a shift in the focus of AML treatment to LSC-directed therapies if the prospect of improved cure rates holds true. In the future, AML treatment should lean toward personalized therapies using combinations of these compounds plus mutation-targeted agents and/or targeted delivery of chemotherapy, aiming at LSC eradication with reduced side effects.

Bone marrow adipocytes (BMA) exert pleiotropic roles beyond mere lipid storage and filling of bone marrow (BM) empty spaces, and we are only now beginning to understand their regulatory traits and versatility. BMA arise from the differentiation of BM mesenchymal stromal cells, but they seem to be a heterogeneous population with distinct metabolisms, lipid compositions, secretory properties and functional responses, depending on their location in the BM. BMA also show remarkable differences among species and between genders, they progressively replace the hematopoietic BM throughout aging, and play roles in a range of pathological conditions such as obesity, diabetes and anorexia. They are a crucial component of the BM microenvironment that regulates hematopoiesis, through mechanisms largely unknown. Previously considered as negative regulators of hematopoietic stem cell function, recent data demonstrate their positive support for hematopoietic stem cells depending on the experimental approach. Here, we further discuss current knowledge on the role of BMA in hematological malignancies. Early hints suggest that BMA may provide a suitable metabolic niche for the malignant growth of leukemic stem cells, and protect them from chemotherapy. Future in vivo functional work and improved isolation methods will enable determining the true essence of this elusive BM hematopoietic stem cell niche component, and confirm their roles in a range of diseases. This promising field may open new pathways for efficient therapeutic strategies to restore hematopoiesis, targeting BMA.

Blood formation, or haematopoiesis, originates from haematopoietic stem cells (HSCs), whose functions and maintenance are regulated in both cell-and cell non-autonomous ways. The surroundings of HSCs in the bone marrow create a specific niche or microenvironment where HSCs nest that allows them to retain their unique characteristics and respond rapidly to external stimuli. Ageing is accompanied by reduced regenerative capacity of the organism affecting all systems, due to the progressive decline of stem cell functions. This includes blood and HSCs, which contributes to age-related haematological disorders, anaemia, and immunosenescence, among others. Furthermore, chronological ageing is characterised by myeloid and platelet HSC skewing, inflammageing, and expanded clonal haematopoiesis, which may be the result of the accumulation of preleukaemic lesions in HSCs. Intriguingly, haematological malignancies such as acute myeloid leukaemia have a high incidence among elderly patients, yet not all individuals with clonal haematopoiesis develop leukaemias. Here, we discuss recent work on these aspects, the ir potential underlying molecular mechanisms, and the first cues linking age-related changes in the HSC niche to poor HSC maintenance. Future work is needed for a better understanding of haematopoiesis during ageing. This field may open new avenues for HSC rejuvenation and therapeutic strategies in the elderly.

The neuroepithelial stem cell protein, or Nestin, is a cytoskeletal intermediate filament initially characterized in neural stem cells. However, current extensive evidence obtained in in vivo models and humans shows presence of Nestin+ cells with progenitor and/or regulatory functions in a number of additional tissues, remarkably bone marrow. This review presents the current knowledge on the role of Nestin in essential stem cell functions, including self-renewal/proliferation, differentiation and migration, in the context of the cytoskeleton. We further discuss the available in vivo models for the study of Nestin+ cells and their progeny, their function and elusive nature in nervous system and bone marrow, and their potential mechanistic role and promising therapeutic value in preclinical models of disease. Future improved in vivo models and detection methods will allow to determine the true essence of Nestin+ cells and confirm their potential application as therapeutic target in a range of diseases.

The neuroepithelial stem cell protein, or Nestin, is a cytoskeletal intermediate filament initially characterized in neural stem cells. However, current extensive evidence obtained in in vivo models and humans shows presence of Nestin

Recently we described that endonuclease inactive DNase I translocated into the nucleus in response to increased endogenous IL-1β expression. Here, we demonstrate impact and function of translocated DNase I in tubular cells. Effect of cytokines on expression level and nuclear localisation of DNase I and corresponding levels of Fas receptor (FasR) and IL-1β were determined by confocal microscopy, qPCR and western blot analyses, in presence or absence of siRNA against IL-1β and DNase I mRNA. Nuclear DNase I bound to the FAS promotor region as determined by chromatin immuno-precipitation analysis. Data demonstrate that; (i) translocation of DNase I depended on endogenous de novo-expressed IL-1β, (ii) nuclear DNase I bound FAS DNA, (iii) FasR expression increased after translocation of DNase I, (iv) interaction of exogenous Fas ligand (FasL) with upregulated FasR induced apoptosis in human tubular cells stimulated with TNFα. Thus, translocated DNase I most probably binds the promoter region of the FAS gene and function as a transcription factor for FasR. In conclusion, DNase I not only executes chromatin degradation during apoptosis and necrosis, but also primes the cells for apoptosis by enhancing FasR expression.

Background: BM HSC accumulate during aging but are functionally impaired; however, it remains debated whether this aging results from HSC-intrinsic and/or -extrinsic mechanisms. Myeloid malignancies are more frequent in the elderly, but whether the aged microenvironment predisposes to these malignancies is unclear. Myeloid-biased HSC and especially platelet-primed HSC expand in aged mice. However, both platelet-primed and unprimed old HSCs exhibit myeloid bias, possibly suggesting a microenvironmental participation. Moreover, some hallmarks of murine hematopoietic aging (like increased platelets) are present in premature aging (Hutchinson-Gilford progeria syndrome, HGPS) and are exacerbated in age-related myeloproliferative neoplasms (MPN), where we found that niche heterogeneity can influence disease progression (ASH abstract ID 113495). Given that aging increases myelopoiesis in physiology, HGPS and MPN (despite their heterogenous genetic background), we hypothesized that shared microenvironmental alterations influence HSC lineage bias during aging

Succinate is an essential intermediate of the tricarboxylic acid cycle that exerts pleiotropic roles beyond metabolism in both physiological and pathological conditions. Recent evidence obtained in mouse models shows its essential role regulating blood cell function through various mechanisms that include pseudohypoxia responses by hypoxiainducible factor-1 alpha activation, post-translational modifications like succinylation, and communication mediated by succinate receptor 1. Hence, succinate links metabolism to processes like gene expression and intercellular communication. Interestingly, succinate plays key dual roles during inflammatory responses, leading to net inflammation or anti-inflammation depending on factors like the cellular context. Here, we further discuss current suggestions of the possible contribution of succinate to blood stem cell function and blood formation. Further study will be required in the future to better understand succinate biology in blood cells. This promising field may open new avenues to modulate inflammatory responses and to preserve blood cell homeostasis in the clinical setting.

Interleukin-1β (IL-1β) is a pleiotropic cytokine that exerts multiple roles in both physiological and pathological conditions. It is produced by different cell subsets, and drives a wide range of inflammatory responses in numerous target cells. Enhanced IL-1β signaling is a common event in patients of hematological malignancies. Recent body of evidence obtained in preclinical models shows the pathogenic role of these alterations, and the promising therapeutic value of IL-1 targeting. In this review, we further highlight a potential contribution of IL-1β linking to complications and autoimmune disease that should be investigated in future studies. Hence, drugs that target IL-1 may be helpful to improve outcome or reduce morbidity in patients. Some of them are FDA-approved, and used efficiently against autoimmune diseases, like IL-1 receptor antagonist. In the clinic, however, this agent seems to have limited properties. Current improved drugs will allow to determine the true potential of IL-1 and IL-1β targeting as therapy in hematological malignancies and their related complications.

We have been made aware of certain irregularities in Figures 1d, 2e, and 6b of the above work that are relevant to its results. We have been advised that, during the course of an internal inquiry and subsequent legal proceedings, corresponding author Dr. Susana Gonzalez was not able to provide original raw data or laboratory notes for any of the experiments represented in these figures to explain or justify the results reported in the article. The remaining co-authors maintain, and we accept, that they did not participate in, and nor were they aware of, this omission. We believe the foregoing constitutes a breach of certain representations and warranties made by the corresponding author Dr. Gonzalez to us with respect to complying with ethical standards and practices governing scientific research and conduct, and of our policy on publishing ethics and integrity. We note that we received, peer-reviewed, accepted, and published the article in good faith based on the purported veracity of these representations and warranties. We have been informed in our decisionmaking to retract the work by the guidance of COPE guidelines on retractions.